EP3470526A2 - Antikörper zur spezifischen bindung an staphylococcus-aureus-alpha-toxin und verwendungsverfahren dafür - Google Patents

Antikörper zur spezifischen bindung an staphylococcus-aureus-alpha-toxin und verwendungsverfahren dafür Download PDF

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EP3470526A2
EP3470526A2 EP18190790.8A EP18190790A EP3470526A2 EP 3470526 A2 EP3470526 A2 EP 3470526A2 EP 18190790 A EP18190790 A EP 18190790A EP 3470526 A2 EP3470526 A2 EP 3470526A2
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nos
antibody
alpha toxin
amino acid
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EP3470526A3 (de
Inventor
Bret SELLMAN
Christine TKACZYK
Lei Hua
Partha Chowdhury
Reena VARKEY
Melissa Damschroder
Li Peng
Vaheh Oganesyan
Jamese Johnson HILLIARD
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MedImmune LLC
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MedImmune LLC
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267—Gram-positive bacteria
    • C07K16/1271—Micrococcaceae (F); Staphylococcaceae (F), e.g. Staphylococcus (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G01N33/56938—Staphylococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
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    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/305—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F)
    • G01N2333/31—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Micrococcaceae (F) from Staphylococcus (G)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/44—Multiple drug resistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/709—Toxin induced
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • antibodies including human, humanized and/or chimeric forms, as well as fragments, derivatives/conjugates and compositions thereof that bind to Staphylococcus aureus alpha toxin.
  • Such antibodies can be useful for detecting and/or visualizing alpha toxin and therefore may be useful in assays and diagnostic methods.
  • Antibodies described herein also interfere with alpha toxin heptamer formation, thereby inhibiting formation of the active pore forming complex, and therefore can be useful for, therapeutic and prophylactic methods..
  • Staphylococcus aureus is a ubiquitous pathogen, and sometimes is an etiological agent of a variety of conditions, ranging in severity from mild to fatal.
  • S. aureus produces a large number of extracellular and cell-associated proteins, many of which are involved in pathogenesis, such as alpha-toxin, beta-toxin, gamma-toxin, delta-toxin, leukocidin, toxic shock syndrome toxin (TSST), enterotoxins, coagulase, protein A, fibrinogen, fibronectin binding protein and the like.
  • Alpha-toxin e.g ., encoded by the hla gene
  • Isolated antibodies presented comprise antibody amino acid sequences disclosed herein, which can be encoded by any suitable polynucleotide. Isolated antibodies sometimes are provided in formulated form.
  • an anti-alpha toxin antibody or fragment binds S. aureus alpha toxin and, thereby partially or substantially alters at least one biological activity of the alpha toxin, for example, oligomerization into the active heptamer complex.
  • VH-CDR2 begins at the fifteenth residue after the end of CDR- H1, includes approximately 16-19 amino acids, and ends at the next glycine residue.
  • VH-CDR3 begins at approximately the thirtieth amino acid residue after the end of VH-CDR2; includes approximately 13-15 amino acids; and ends at the sequence M-D-V.
  • VL-CDR1 begins at approximately residue 24 ( i.e ., following a cysteine residue); includes approximately 10-15 residues; and ends with the sequence Y-V-S.
  • VL-CDR2 begins at approximately the sixteenth residue after the end of VL-CDR1 and includes approximately 7 residues.
  • an isolated antibody or antigen-binding fragment thereof immunospecifically binds alpha toxin and comprises a VH CDR3 comprising an amino acid sequence identical to, or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: SEQ ID NO: 9, 12, 15, 18, 16, 65, 66, 67, 71, 72, 76 or 78, where the antibody or antigen binding fragment alleviates or eliminates dermonecrosis.
  • Stringent hybridization temperatures can also be altered (i.e., lowered) with the addition of certain organic solvents, formamide for example.
  • Organic solvents like formamide, reduce the thermal stability of double-stranded polynucleotides, so that hybridization can be performed at lower temperatures, while still maintaining stringent conditions and extending the useful life of nucleic acids that may be heat labile.
  • Determination of binding affinity can be measured using the specific techniques described further in the Example section, see Example 1, and methods known in the art.
  • One example of such a method includes measuring the disassociation constant "K d " by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen as described by the following assay that measures solution binding affinity of Fabs for antigen by equilibrating Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate.
  • RIA radiolabeled antigen binding assay
  • an anti-alpha toxin antibody or fragment alters the biological properties of alpha toxin and/or alpha toxin expressing cells.
  • an anti-alpha toxin antibody or fragment neutralizes the biological activity of alpha toxin by binding to the polypeptide and inhibiting the assembly of alpha toxin monomers into a transmembrane pore (e.g., alpha toxin heptamer).
  • Neutralization assays can be performed using methods known in the art using, in some circumstances, commercially available reagents.
  • mice are immunized against the antigen, immunogenic conjugates, or derivatives by combining an appropriate concentration of antigen or conjugate with adjuvant and injecting the solution at multiple sites. Immunizations can also be performed as described in Example 1 (immunization/hybridoma generation).
  • Additional cell lines that may be used as hosts for expression of recombinant antibodies include, but are not limited to, insect cells (e . g ., Sf21/Sf9, Trichoplusia ni Bti-Tn5b1-4) or yeast cells ( e . g ., S. cerevisiae, Pichia, US7326681 ; etc), plants cells ( US20080066200 ); and chicken cells.
  • an antibody molecule may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e . g ., ion exchange, affinity, particularly by affinity for the specific antigens Protein A or Protein G, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • chromatography e . g ., ion exchange, affinity, particularly by affinity for the specific antigens Protein A or Protein G, and sizing column chromatography
  • centrifugation e.g ion exchange, affinity, particularly by affinity for the specific antigens Protein A or Protein G, and sizing column chromatography
  • differential solubility e.g chromatography
  • the antibodies of the present technology or fragments thereof may be fused to heterologous polypeptide sequences (referred to herein as "tags") described above or otherwise known in the art to facilitate purification.
  • an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus.
  • one or more VH genes, one or more DH genes, one or more JH genes, a mu constant region, and usually a second constant region are formed into a construct for insertion into an animal.
  • Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (Medlmmune (formerly CAT), Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (Medlmmune (formerly CAT)), yeast display, and the like.
  • the phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunized donors.
  • the diversification processes may also generate some structural liabilities or these structural liabilities may exist within germline sequences contributing to the heavy and light chain variable domains. Regardless of the source, it may be desirable to remove potential structural liabilities that may result in instability, aggregation, heterogeneity of product, or increased immunogenicity. Examples of undesirable liabilities include unpaired cysteines (which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation), N-linked glycosylation sites (resulting in heterogeneity of structure and activity), as well as deamidation ( e . g ., NG, NS), isomerization (DG), oxidation (exposed methionine), and hydrolysis (DP) sites.
  • unpaired cysteines which may lead to disulfide bond scrambling, or variable sulfhydryl adduct formation
  • N-linked glycosylation sites resulting in heterogeneity of structure and activity
  • deamidation e . g ., NG, NS
  • the antibody of choice is a single-chain Fv fragment (scFv).
  • the antibody is not a Fab fragment.
  • Fv and scFv are the only species with intact combining sites that are devoid of constant regions; thus, they are suitable for reduced nonspecific binding during in vivo use.
  • scFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an scFv.
  • an antibody can be modified to produce fusion proteins; i.e., the antibody, or a fragment thereof, fused to a heterologous protein, polypeptide or peptide.
  • the protein fused to the portion of an antibody is an enzyme component of Antibody-Directed Enzyme Prodrug Therapy (ADEPT).
  • ADPT Antibody-Directed Enzyme Prodrug Therapy
  • “Effector cells” are leukocytes that express one or more FcRs and perform effector functions.
  • the cells express at least Fc ⁇ , FC ⁇ RII, Fc ⁇ RIII and/or Fc ⁇ RIV and carry out ADCC effector function.
  • Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells and neutrophils.
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • monocytes monocytes
  • cytotoxic T cells cytotoxic T cells and neutrophils.
  • Fc receptor or “FcR” are used to describe a receptor that binds to the Fc region of an antibody.
  • the FcR is a native sequence human FcR.
  • the FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, Fc ⁇ RIII, and Fc ⁇ RIV subclasses, including allelic variants and alternatively spliced forms of these receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor") and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • Anti-alpha toxin antibodies and fragments herein comprising a variant Fc region are also referred to here as "Fc variant antibodies.”
  • native refers to the unmodified parental sequence and the antibody comprising a native Fc region is herein referred to as a "native Fc antibody”.
  • the variant Fc region exhibits a similar level of inducing effector function as compared to the native Fc region.
  • the variant Fc region exhibits a higher induction of effector function as compared to the native Fc.
  • the variant Fc region exhibits lower induction of effector function as compared to the native Fc.
  • an Fc variant where the Fc region comprises at least one substitution selected from the group consisting of 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241 L, 241Y, 241E, 241 R.
  • an Fc variant antibody where the Fc region comprises at least one modification (e.g., amino acid substitutions, amino acid insertions, amino acid deletions) at one or more positions selected from the group consisting of 234, 235 and 331.
  • the non-naturally occurring amino acids are selected from the group consisting of 234F, 235F, 235Y, and 331S.
  • the Fc region comprises at least one non-naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332.
  • the non-naturally occurring amino acids are selected from the group consisting of 239D, 330L and 332E.
  • the Fc variants herein may be combined with other known Fc variants as known in the art.
  • Other modifications and/or substitutions and/or additions and/or deletions of the Fc domain can be introduced.
  • A549 cells were maintained in a 5% CO 2 37°C incubator in RMPI supplemented with non essential amino acid, glutamine and 10% fetal bovine serum. Cells were washed once with Hank's balanced media, and plated at 10 4 /well under 50 ⁇ l in RPMI, 5% FBS, and incubated at 37°C with 5% CO 2 for 20 hr. Anti-AT mAbs were added to a 96-well plate at 80 ⁇ g/mL in RPMI and the samples serially diluted (two-fold) in RPMI. An irrelevant IgG1 (R347) was included as an isotype control.
  • Each anti-AT IgG was first injected over the capture and reference surfaces at a flow rate of 50 ⁇ L/min. Once the binding of the captured IgG had stabilized, a single concentration of the nAT protein was injected over both surfaces, at a flow rate of 50 ⁇ L/min. The resultant binding response curves was used to determine the association phase data. Following the injection of the nAT, the flow was then switched back to instrument buffer for 10 minutes to permit the collection of dissociation phase data followed by a 1 minute pulse of 10mM glycine, pH 1.5 to regenerate the IgG capture surface on the chip. Binding responses from duplicate injections of each concentration of nAT were recorded against all anti-AT IgGs.
  • the IC 50 was calculated using the RBC hemolytic assay with S . aureus alpha toxin at 0.1mg/ml
  • Presence of the SDS-resistant heptamer is readily apparent at the top of the gel shown in Figure 12 , in lanes 6 and 7 (e.g., mAb9D7.3 and no IgG control lane, respectively). All of the inhibitory mAbs ablated heptamer formation, whereas an irrelevant isotype control ( e . g ., Lane 6; 9D7.3) had no effect.
  • the inhibition of oligomerization activity was confirmed using mAbs 2A3.1, 10A7.5 and 12B8.19 in an oligomerization assay on rabbit RBC ghosts, as illustrated in the representative western blots shown in Figures 13A and 13B .
  • Example 10 Representative Amino Acid and Nucleotide Sequences for Antibodies that Specifically Bind to S. aureus Alpha Toxin
  • the segment corresponding to aa 248-277 showed impact on binding and also contained the X-ray structural contact residues identified as comprising aa 261-272 (in which T263, N264, and K266 are actual contacting residues) ( Figure 20 ).
  • the crystal structure revealed another segment corresponding to aa 173-201 in which D183, W187, and N188 are actual contacting residues ( Figure 20 ).
  • the chimeric variant that contained this particular segment (KO_148-205) still exhibited good binding to LC10 YTE. This is likely attributable to this particular region's high sequence homology (52% identity and 63% similarity) between alpha toxin and LukF-PV.
  • the amino acids around the contacting residues (aa 179-193) share even higher homology (67% identity), while, in contrast, the entire sequence shares only 25% identity.
  • mice Seven-week old female C57BL/6J mice were infected intranasally with 2e8 cfu (LD100) of methicillin-resistant Staphylococcus aureus USA300. Vancomycin and LC-10 were individually titrated to determine the optimal and sub-efficacious doses.
  • LD100 methicillin-resistant Staphylococcus aureus USA300.
  • Vancomycin and LC-10 were individually titrated to determine the optimal and sub-efficacious doses.
  • mice were treated one hour post-infection, with a single intraperitoneal dose of LC-10, or the negative control antibody R347 (15 mg/kg). Vancomycin treatment in mono or dual therapy was initiated 1 hr postinfection and administered BID subcutaneously 3 days. The percent survival for all treated groups was determined at the end of seven days. Survival curves were analyzed using the Mandel-Cox log-rank test.

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